The immune system is a double-edged sword. While its primary role is to fight infections, it can also become overactive, leading to problems like allergies and autoimmune diseases.
For example, the part of the immune system responsible for resisting parasites acts by releasing white blood cells called eosinophil granulocytes into the blood. But elevated eosinophil levels are also responsible for allergic reactions, including most forms of asthma, gastrointestinal diseases, blood disorders, and cancers.
Now a study, led by Dr. Ariel Munitz of the Department of Clinical Microbiology and Immunology at the Sackler School of Medicine at Tel Aviv University, and conducted by graduate students Netali Baruch Morgenstern and Dana Shik, has found a mechanism that pushes eosinophils to die before they get into the blood and wreak havoc. The discovery is a breakthrough in science's understanding of the immune system and suggests powerful new treatments for eosinophilic diseases such as asthma.
"We've discovered an important and powerful pathway that works to kill eosinophils," says Dr. Munitz. "The fundamental knowledge we have gained may one day yield even bigger results and therapies."
Published online in Nature Immunology in November, the research was funded in part by the United States-Israel Binational Science Foundation, the Israel Science Foundation, the Israel Cancer Research Fund, and the Fritz Thyssen Stiftung. The Division of Allergy and Immunology at the Cincinnati Children's Hospital Medical Center collaborated on it.
The body's tug-of-war
The level of eosinophils in the blood is relatively low in healthy people, accounting for just 2 to 5 percent of white blood cells in circulation. But in eosinophilic disorders, a signalling protein called interleukin 5, or IL-5, triggers a rush of eosinophils from the bone marrow, where they are produced, and into the blood, where they are transported to various organs. IL-5 has lately been investigated as a new target for asthma medications, some of which have proven effective in clinical trials.
Analyzing the bone marrow of mice, the researchers found that the expansion of eosinophils caused by IL-5 is actually part of a broader mechanism that regulates the lifecycle of the cells. While IL-5 commands eosinophils to expand and enter the bloodstream, a cell receptor called paired immunoglobulin-like receptor A, or PIR-A, commands eosinophils to die. So eosinophils are in a constant "tug-of-war" between survival signals delivered by IL-5 and death orders delivered by PIR-A.
Although the death order by PIR-A is dominant, it is never executed. Eosinophils express another receptor, called PIR-B, which closely resembles PIR-A and inhibits its actions. In order for PIR-A to carry out its death order to the cell, PIR-B must be shut down.
"PIR-A is always inhibited by PIR-B from the very early stages of eosinophil development," says Dr. Munitz. "We had to remove the expression of PIR-B from the cells to see PIR-A's powerful effects."
Two new approaches to nip disease in the bud
After identifying the mechanism in cell culture systems, the researchers verified that it also operates in mice. As expected, they found that asthmatic mice without PIR-B in their bodies had very little expansion of eosinophils into their blood and lungs and therefore less asthmatic inflammation in their lungs than normal mice. Unhindered by PIR-B, PIR-A appeared to keep eosinophils from reaching harmful levels in their bodies. Because human eosinophils also express PIR-like molecules, there is good reason to believe the same mechanism works in people.
In addition to advancing knowledge of eosinophils -- a basic and important cell type -- the researchers' work opens up two new avenues for treating eosinophilic disorders. Instead of lowering IL-5 levels to try to reduce eosinophil expansion, scientists can now target PIR-A to enhance its ability to kill eosinophils. Alternatively, they could weaken PIR-B so that it inhibits PIR-A less.
The researchers have preliminary evidence that PIR-B inhibits other mechanisms that drive cell death. Identifying them is the focus of their current research.
- Netali Ben Baruch-Morgenstern, Dana Shik, Itay Moshkovits, Michal Itan, Danielle Karo-Atar, Carine Bouffi, Patricia C Fulkerson, Diana Rashkovan, Steffen Jung, Marc E Rothenberg, Ariel Munitz. Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5–induced eosinophil development. Nature Immunology, 2013; DOI: 10.1038/ni.2757
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